Anti-bradykinin b2 receptor (bkb2r) monoclonal antibody

Abstract

The present invention relates generally to anti-bradykinin B2 receptor (BKB2R) antibodies and methods for making and using them. In particular, the anti-BKB2R antibodies having the variable region sequences described herein are useful for altering one or more of BKB2R of and/or GSK-3 signaling pathways for the treatment of diseases, disorders and conditions such as cancer, diabetes, cardiovascular disorders and other conditions.

1 - 34 . (canceled) 
     
     
         35 . A method for lowering blood glucose in a patient in need thereof, comprising administering to the patient an antibody, or antigen-binding fragment thereof, that specifically binds to a bradykinin B2 receptor (BKB2R) peptide epitope having the sequence set forth in SEQ ID NO:73 or 74. 
     
     
         36 . The method of  claim 35 , where the patient has one or more of insulin resistance, impaired glucose tolerance (IGT), impaired insulin secretion, or excessive hepatic glucose output. 
     
     
         37 . The method of  claim 35 , where the patient has diabetes. 
     
     
         38 . The method of  claim 37 , where the patient has type 2 diabetes. 
     
     
         39 . The method of  claim 35 , where the patient is human. 
     
     
         40 . The method of  claim 35 , where the antibody, or antigen-binding fragment thereof, specifically binds to the peptide epitope of SEQ ID NO:73. 
     
     
         41 . The method of  claim 35 , where the antibody, or antigen-binding fragment thereof, is selected from the group consisting of a single chain antibody, a ScFv, a univalent antibody lacking a hinge region, and a minibody. 
     
     
         42 . The method of  claim 35 , where the antibody is a Fab or a Fab′ fragment. 
     
     
         43 . The method of  claim 35 , where the antibody is a F(ab) 2  fragment. 
     
     
         44 . The method of  claim 35 , where the antibody is a whole antibody. 
     
     
         45 . The method of  claim 35 , where the antibody comprises a human IgG Fc domain. 
     
     
         46 . The method of  claim 45 , where the antibody comprises a human IgG2 Fc domain. 
     
     
         47 . The method of  claim 35 , where the antibody is humanized. 
     
     
         48 . The method of  claim 35 , where the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region that comprises VHCDR1, VHCDR2 and VHCDR3 amino acid sequences; and a light chain variable region that comprises VLCDR1, VLCDR2 and VLCDR3 amino acid sequences, wherein at least one of:
 (1) (A) VHCDR1, VHCDR2 and VHCDR3 comprise, respectively, the amino acid sequences of (i) SEQ ID NOS:19, 20 and 21, or (ii) SEQ ID NOS:22, 23 and 24; and (B) VLCDR1, VLCDR2 and VLCDR3 comprise, respectively, the amino acid sequences of (i) SEQ ID NOS:34, 35 and 36, (ii) SEQ ID NOS:37, 38 and 39, or (iii) SEQ ID NOS:40, 41 and 42; including variants thereof where at least one of said VHCDR or VLCDR amino acid sequences is modified by one amino acid substitution; or   (2) (A) VHCDR1, VHCDR2 and VHCDR3 comprise, respectively, the amino acid sequences of (i) SEQ ID NOS:13, 14 and 15, or (ii) SEQ ID NOS:16, 17 and 18; and (B) VLCDR1, VLCDR2 and VLCDR3 comprise, respectively, the amino acid sequences of (i) SEQ ID NOS:28, 29 and 30, or (ii) SEQ ID NOS:31, 32 and 33; including variants thereof where at least one of said VHCDR or VLCDR sequences is modified by one amino acid substitution.   
     
     
         49 . The method of  claim 35 , where VHCDR1, VHCDR2 and VHCDR3 comprise, respectively, the amino acid sequences of (i) SEQ ID NOS:19, 20 and 21, or (ii) SEQ ID NOS:22, 23 and 24; and where VLCDR1, VLCDR2 and VLCDR3 comprise, respectively, the amino acid sequences of (i) SEQ ID NOS:34, 35 and 36, (ii) SEQ ID NOS:37, 38 and 39, or (iii) SEQ ID NOS:40, 41 and 42. 
     
     
         50 . The method of  claim 35 , where VHCDR1, VHCDR2 and VHCDR3 comprise, respectively, the amino acid sequences of SEQ ID NOS:16, 17 and 18, and where VLCDR1, VLCDR2 and VLCDR3 comprise, respectively, the amino acid sequences of SEQ ID NOS:31, 32 and 33. 
     
     
         51 . The method of  claim 35 , where VHCDR1, VHCDR2 and VHCDR3 comprise, respectively, the amino acid sequences of SEQ ID NOS:19, 20 and 21, and where VLCDR1, VLCDR2 and VLCDR3 comprise, respectively, the amino acid sequences of SEQ ID NOS:34, 35 and 36. 
     
     
         52 . The method of  claim 35 , where VHCDR1, VHCDR2 and VHCDR3 comprise, respectively, the amino acid sequences of SEQ ID NOS:19, 20 and 21, and where VLCDR1, VLCDR2 and VLCDR3 comprise, respectively, the amino acid sequences of SEQ ID NOS:37, 38 and 39. 
     
     
         53 . The method of  claim 35 , where VHCDR1, VHCDR2 and VHCDR3 comprise, respectively, the amino acid sequences of SEQ ID NOS:19, 20 and 21, and where VLCDR1, VLCDR2 and VLCDR3 comprise, respectively, the amino acid sequences of SEQ ID NOS:40, 41 and 42. 
     
     
         54 . The method of  claim 35 , where VHCDR1, VHCDR2 and VHCDR3 comprise, respectively, the amino acid sequences of SEQ ID NOS:22, 23 and 24, and where VLCDR1, VLCDR2 and VLCDR3 comprise, respectively, the amino acid sequences of SEQ ID NOS:34, 35 and 36. 
     
     
         55 . The method of  claim 35 , where VHCDR1, VHCDR2 and VHCDR3 comprise, respectively, the amino acid sequences of SEQ ID NOS:22, 23 and 24, and where VLCDR1, VLCDR2 and VLCDR3 comprise, respectively, the amino acid sequences of SEQ ID NOS:37, 38 and 39. 
     
     
         56 . The method of  claim 35 , where VHCDR1, VHCDR2 and VHCDR3 comprise, respectively, the amino acid sequences of SEQ ID NOS:22, 23 and 24, and where VLCDR1, VLCDR2 and VLCDR3 comprise, respectively, the amino acid sequences of SEQ ID NOS:40, 41 and 42.